Molecular recognition at the opioid-modulating neuropeptide FF receptor 1

The NPFFR1 (neuropeptide FF receptor 1) responds to endogenous RF-amide peptides like NPFF (Neuropeptide FF) and RFRP-3 (RF-amide related peptide-3), both containing a conserved C-terminal Arg-Phe-NH motif (Quillet et al., 2016).In mammals, NPFF-related peptides are derived from two precursors (Bonini et al., 2000): pro-NPFF A , yielding peptides such as NPFF and NPAF (Neuropeptide AF) that prefer binding to NPFFR2 (neuropeptide FF receptor 2); and pro-NPFF B , yielding RFRP-3, which favors NPFFR1 (Quillet et al., 2016).NPFFR1 primarily couples to inhibitory Gi/o proteins and regulates diverse physiological functions, including energy homeostasis, reproduction, substance abuse disorders, cardiovascular control, anxiety, food intake, and pain (Nguyen et al., 2020).Previous studies have suggested that NPFF receptors and their endogenous ligands are involved in the regulation of pain perception and opioid-induced antinociception (Ayachi and Simonin, 2014).The two receptors (NPFFR1 and NPFFR2) may exert opposing pain modulation effects, which may be attributed to the functional differences between NPFFR1 and NPFFR2.While NPFFR1 may act as an anti-opioid modulator, NPFFR2 may instead exert antinociceptive and opioid-potentiating effects (Malin et al., 2015).Blocking NPFFR1 alone can prevent analgesic tolerance and dependence, enhance opioid antinociceptive effects, and reduce opioid withdrawal symptoms.However, due to the lack of highly selective agonists and antagonists of NPFFR1 vs NPFFR2, their precise mechanism on opioid modulation is yet to be unraveled.RFRP-3 and NPFF are endogenous ligands of NPFFR1, both sharing the fouramino acid sequence PQRF at their C-termini (Fig. 1A and1B).However, the